Liver Disease in WTC Responders: This project provides the first systematic investigation of liver disease in the World Trade Center (WTC) general responder cohort (GRC). Currently, WTC responders are not screened for liver diseases, although they were heavily exposed to dust, airborne particulate matter, and chemicals known to cause liver toxicity in other populations. Studies in animals confirm the hepatotoxic effects of air- borne particulate matter (PM2.5) and chemicals. Toxic exposures have been associated with non-alcoholic steatohepatitis (NASH), a progressive form of non-alcoholic fatty liver disease (NAFLD) that can lead to liver failure and liver cancer. This project addresses the need for a greater understanding of NASH and other pro- gressive liver diseases in WTC responders. Our Preliminary Results suggest that WTC exposure is a risk fac- tor for liver steatosis, one of the defining features of NASH (the other feature of greatest clinical significance is fibrosis). Because liver disease is often a silent killer that remains undiagnosed until irreversible damage has occurred, it is essential to screen for liver disease proactively. During the early and curable stages, many liver diseases are asymptomatic. Advanced liver disease can present catastrophically as metastatic liver cancer. We expect to find that the WTC attack exposed responders to hepatotoxins and caused steatosis and fibrosis. Uncovering previously unrecognized liver disease will allow WTC responders to be counseled and treated. Aim I: The goal is to test the hypothesis that WTC exposure is a risk factor for liver disease by comparing GRC members (n=400) to a control group of non-responders (n=400) using multivariable linear regression to ana- lyze liver fat (SubAim 1) and liver fibrosis (SubAim 2). Liver fat (steatosis) will be estimated using FibroScan- CAP and CT attenuation values; the correlation between the two methodologies will be analyzed (SubAim 3). WTC providers will be notified of high risk patients (those with both elevated fat and fibrosis), enhancing care. Aim II: The goals are to develop enabling technology to computationally estimate liver fat content from low- dose non-contrast chest CT images (SubAim 1), to apply this technology to existing images of 5000 GRC members (SubAim 2), and to use general linear models with pairwise comparisons to test the hypothesis that there is a linear dose-response relationship between the intensity of WTC exposure and liver fat (SubAim 3). Aim III: The goals are to determine the prevalence of and risk factors for advanced fibrosis/cirrhosis in the GRC (SubAim 1), to develop advanced medical informatics tools to computationally identify patients with NASH, HCV, and/or alcoholic liver disease (SubAim 2), to combine these tools with manual chart review to de- tect and analyze liver diseases, including liver cancer, among the estimated 2000 GRC members with in-depth medical, pharmaceutical, and claims data; and to provide feedback to providers, enhancing care (SubAim3). The studies will yield unprecedented data about WTC exposure and liver disease and produce innovative digi- tal technologies. They are likely to uncover (previously overlooked) liver disease, immediately improving care.